Nikita Maruti Gaikwad, Pravin Digambar Chaudhari, Karimunnisa Sameer Shaikh,Somdatta Yashwant Chaudhari, Rasha Mohammed Saleem, Mohammad Algahtani, Ahmed E. Altyar, Ghadeer M. Albadrani, Mohamed Kamel, Mohamed M. Abdel-Daim
Abstract
Drug repurposing is the finding new activity of the existing drug. Recently, Albendazole’s well-known antihelmintic has got the attention of an anticancer drug. Plausible evidence of the interaction of Albendazole with one of the types of tyrosine kinase protein receptor, vascular endothelial growth factor receptor-2 (VEGFR-2) is still not well understood. Inhibition of the VEGFR-2 receptor can prevent tumor growth. The current study investigated the interaction of Albendazole with VEGFR-2.It was found that the said interaction exhibited potent binding energy ΔG = -7.12 kcal/mol, inhibitory concentration (Ki) = 6.04 μM, and as positive control comparison with standard drug (42Q1170A) showed ΔG = -12.35 kcal/mol and Ki = 881 μM. The key residue Asp1046 was formed involved hydrogen bonding with Albendazole. The molecular dynamics simulation study revealed the stable trajectory of the VEGFR-2 receptor with Albendazole bound complex having significant high free energy of binding as calculated from Molecular Mechanics Generalized Born and Surface Area study ΔG = -42.07±2.4 kcal/mol. The binding energy is significantly high for greater stability of the complex. Principal component analysis of molecular docking trajectories exhibited ordered motion at higher modes, implying a high degree of VEGFR-2 and Albendazole complex stability as seen with the standard drug 42Q.
Introduction
Cancer is most deadly disease in the world. Cancer treatment is the most difficult task for researchers. As a result, researchers devote time and resources to discovering and developing new therapies for various cancers. Nonetheless, cancer occurrence is anticipated to rise by even more over 50% in the next years, which is regrettable. Ovarian cancer is the seventh leading cause of mortality and morbidity in women globally. There are many types of ovarian cancer, both common and uncommon, such as epithelial ovarian cancer, germ cell tumour, primary peritoneal cancer, fallopian tube cancer, stromal cell tumour, and ovarian cancer [1]. In general, cancer is treated using traditional methods that target the DNA of all cells; however, one important disadvantage of this treatment is that it also affects healthy cells. To address this issue, targeted drug treatment has been established to release a drug to a specific site of receptor while minimizing cell toxicity [2]. To design targeted treatments, scientists must first discover the genetic alterations that allow a cancer cell to mutated. A protein found in cancer cells may become promising approach to target tumor instead of healthy cell [3]. In the treatment of cancer, a broad variety of targeted therapies have been tried. Various drug administration techniques, such as hormone treatments, signal transduction inhibitors, gene expression modulators, apoptosis inducers, angiogenesis inhibitors, immunotherapies, and toxin delivery vehicles, have been shown to have stronger therapeutic action [3].
Materials and methods
VEGFR-2 protein preparations
The human VEGFR2 kinase domain crystal structure comprises 359 amino acids and a novel pyrrolopyrimidine inhibitor (1-2-fluoro-4-[(5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl)oxy]phenyl-3-[3-(trifluoromethyl)phenyl]urea) 42Q (PDB ID: 3VHE) [18]. It was obtained from the "Protein Data Bank" (https://www.rcsb.org/) and cleaned with the "Biovia Discovery Studio Visualizer" (https://disCover.3ds.com/discovery-studio-visualizer-download). Swiss-pdb viewer 4.1.0 and UCSF Chimera v1.15 were used to optimizing the retrieved protein. Intrinsic water molecules were first removed from the protein’s pocket area and the co-crystallized ligand. Polar hydrogens were inserted, which was proceeded by energy reduction utilizing conjugate gradient and the steepest method. Gasteiger charge potentials were introduced after minimization. All of the protein’s heteroatoms are also eliminated, which may interfere with the receptor’s binding site and cause problems with protein-ligand interaction. The macromolecule’s output structure is then stored in pdbqt format.
Results
Molecular target predictions
Molecular target studies were projected based on their similarities to known compounds to estimate their targets to conduct the molecular mechanisms behind a certain phenotypic or bioactivity and rationalize any side effects. The top 50 results of the closely related receptors in 2D/3D were shown as a pie chart based on Target, Popular Name, Uniprot ID, ChEMBL-ID, Target Class, Probability, and Reported actives (Fig 2). As can be seen, ABZ predicts 26% Kinase receptor, 18% family α G protein-coupled receptor, and 18% Enzymes while 42Q has 34% Kinases and 14% protease, and 6% Enzymes.
Discussion
Analysis of principal component (PCA) with free energy surface/landscape (FEL)
Principal component analysis (PCA) of the MD simulation trajectories for ABZ bound to the VEGFR2 kinase domain was analyzed to interpret the randomized, global motion of the atoms of amino acid residues along with free energy. This analysis interprets the more flexible scattered trajectories due to the protein structure’s randomness due to non-correlated global motion. The internal coordinate’s mobility into three-dimensional space in the spatial time of 200 ns was recorded in a covariance matrix. The rational motion of each trajectory is interpreted in the form of orthogonal sets or Eigenvectors. MD simulation trajectory of Cα atoms of ABZ bound to VEGFR2 kinase domain displayed more unordered orientation in PC1 and PC2 modes where, the free energies are not converged localized (Fig 6A, blue, as per scale). Following this, PC2 and PC3 mode displayed better order Eigenvalues for the trajectories with partially ordered free energy surface (Fig 6B). The Eigenvectors displayed a less scattered, more correlated and partially converged free energy surface of the last 50 trajectories (Fig 6B).
Conclusion
Albendazole approved by FDA for therapeutic usage as an anthelmintic found to act as VEGFR-2 inhibitor, that represent potential treatment option after investigation. Albendazole binds with conserved residues presents in substrate binding pocket and forms remarkable interactions. Molecular docking and dynamics study are well-established computational techniques that predict drugs’ affinity and stability towards the receptor. The current investigation on Albendazole interaction with VEGFR-2 using molecular docking suggested the achievable interaction and possible inhibition. In addition, molecular dynamics simulation suggested greater stability of VEGFR-2 with Albendazole like a standard cocrystal ligand 42Q with plausible and significant binding energies. The results of this study confirm initial reports however additional investigation necessary to check the efficacy of drug by in vitro and in vivo studies followed by clinical trials against ovarian cancer patients. But publishing this information in public domain may help community to fight with ovarian cancer if any potential investigator proceeds for trials. We recommend that this drug candidate be experimentally tested and used as a starting point for further design of a high efficient drug.
Acknowledgments
The authors are grateful to P.E Society’s Modern College of Pharmacy, Nigdi, Pune, for providing the necessary research facilities.
Citation: Gaikwad NM, Chaudhari PD, Shaikh KS, Chaudhari SY, Saleem RM, Algahtani M, et al. (2023) Albendazole repurposing on VEGFR-2 for possible anticancer application: In-silico analysis. PLoS ONE 18(8): e0287198. https://doi.org/10.1371/journal.pone.0287198
Editor: Arabinda Ghosh, Gauhati University, INDIA
Received: October 25, 2022; Accepted: June 1, 2023; Published: August 16, 2023
Copyright: © 2023 Gaikwad et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting information files.
Funding: This study was supported by Princess Nourah bint Abdulrahman University Researchers Supporting Project number (PNURSP2023R30), Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia. The funders have an indispensable role in revising, reviewing, and finalizing the manuscript throughout.
Competing interests: NO authors have competing interests.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0287198
